High Fat Diet-Dependent & Intestinal Epithelial Exosome-Mediated Induction of Non-Alcoholic Fatty Liver Disease

Overview

The overall goal is to define the role of hepatocyte exosomes in high fat diet mediated promotion of DEN-induced HCC in a mouse liver cancer model. Further, the merits of using novel edible fruit exosomes as a delivery vehicle for targeted delivery of an anti-inflammatory agent to inflammatory cells for treatment of HCC will be determined. Preliminary data indicate that intestinal exosomes are present in peripheral blood of obese mice and obese individuals, and that hepatocyte exosomes from mice fed a high-fat diet (HFD) promote liver inflammatory responses in a mouse model. These data implicate the production of hepatocyte exosomes in the inflammatory responses associated with development of hepatocellular carcinoma. Preliminary data indicate that HFD-exosomes carry high levels of sumoylated CSN5 (sumo-CSN5 or COP9 signalosome complex subunit 5) and that delivery of sumo-CSN5 to immature myeloid cells promotes degradation of Jak3, a process that is essential for differentiation of myeloid cells. Additional preliminary studies pinpointed production of sumo-CSN5 as a critical pathogenic step in exosome-mediated induction of liver inflammatory cytokines. In hepatocytes, ErK1/2 kinase is activated by soluble factor(s) from the supernatant of homogenized livers of high fat-fed mice and causes disassociation of Senp1 which acts as a suppressor of sumoylation of CSN5, thereby promoting production of sumo-CSN5. This process is inhibited by curcumin, which is known to inhibit ErK1/2 activation.

Hypothesis

blocksactivation of Interaction leads to Hypothetical Model of Role of Sumo-CSN5 of HFD-exosome- mediated Immunosuppression Aim 2: in HFD hepatocytes, pERK1/2 leads CSN-5 + Sumo-1 to activate into Sumoylated CSN-5Aim 2 CSN5 + Sumo1 CSN5 Sumoylation leads to Aim 1 Exosomes deliver sumoylated CSN-5 rich to immune cells Exosomes Sumoylated CSN-5 in immune cells degrade Jak3 Immune cells Sumoylated CSN5 Jak3 Degradation Aim 3 Curcumin pERK1/2 Sumoylated CSN5

High fat diet-mediated activation of hepatocyte ERK1/2 leads to the enhancement of sumoylation of CSN5. Sumoylated CSN5-enriched exosomes produced by hepatocytes are taken up by myeloid cells, resulting in exosomal sumoylated CSN5-dependent immunosuppression and promotion of tumor growth.

About Researcher

Principal Investigator

Zhong-bin Deng

Zhong-bin Deng, PhD

Assistant Professor of Medicine

E-mail Dr. Deng

Education

PostDoc
University of Alabama, Birmingham
Medical College of Georgia
PhD
Viral Immunology, Soochow University, Suzhou, China